Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial.

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Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial.

JAMA. 2017 May 23;317(20):2088-2096

Authors: Moran GJ, Krishnadasan A, Mower WR, Abrahamian FM, LoVecchio F, Steele MT, Rothman RE, Karras DJ, Hoagland R, Pettibone S, Talan DA

Importance: Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, β-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity.
Objective: To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone.
Design, Setting, and Participants: Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012.
Interventions: Cephalexin, 500 mg 4 times daily, plus trimethoprim-sulfamethoxazole, 320 mg/1600 mg twice daily, for 7 days (n = 248 participants) or cephalexin plus placebo for 7 days (n = 248 participants).
Main Outcomes and Measures: The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%.
Results: Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, -1.0% to 15.5%; P = .07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly.
Conclusions and Relevance: Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.
Trial Registration: clinicaltrials.gov Identifier: NCT00729937.

PMID: 28535235 [PubMed - indexed for MEDLINE]


  1. Hi,
    I see that you do virtual journal clubs. I am currently doing research and was wondering if you have the journal club available for others to view? I would love to hear/read thoughts on this trial.
    Thank you,
    Eric Garcia

  2. Thanks for asking – the discussion of the article happens right here! The full text of the article is available at this link: http://jamanetwork.com/journals/jama/fullarticle/2627970

    If you do not have individual access to it, you may be able to work with a local library or university to get access.

    The study is a randomized, placebo-controlled design enrolling patients with uncomplicated, non-purulent cellulitis. The hypothesis was that adding trimethoprim/sulfamethoxazole (TMP) to cephalexin would improve cure rates because of better MRSA coverage. Although common, this practice is a weak recommendation in the IDSA guidelines:

    The study failed to find a statistically significant difference of adding TMP among patients who completed therapy and follow-up. The caveat is that many patients who did not receive TMP either dropped out of the trial (due to failure to follow up or due to treatment failure) or were non-adherent with therapy. When all of these patients were included and assumed to have failed therapy (mITT-1), the group with TMP had a non-significant trend toward better outcome. Since this intention to treat design may more accurately reflect “real-world” experience, the study leaves open the question of whether there may be a benefit to adding TMP to non-purulent cellulitis.

    Do you routinely add MRSA coverage when treating cellulitis?

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